Identifying ligands directly interacting with target protein in medicinal herbs by metabolomic analysis of T2-filtered HSQC spectra.

A protocol for efficiently identifying ligands directly interacting with a target protein in complex extracts of medicinal herbs was proposed by combining an adapted 2D perfect-echo Carr-Purcell-Meiboom-Gill heteronuclear single quantum correlation (PE-CPMG HSQC) spectrum with metabolomic analysis. PE-CPMG HSQC can suppress the signal interference from the target protein, allowing more accurate peak quantification than conventional HSQC. Inspired from untargeted metabolomics, regions of interest (ROIs) are constructed and quantified for the mixture or complex extract samples with and without a target protein, and then a binding index (BI) of each ROI is determined. ROIs or corresponding peaks significantly perturbed by the presence of the target protein (BI ≥1.5) are detected as differential features, and potential binding ligands identified from the differential features can be equated with bioactive markers associated with the 'treatment' of the target protein. Quantifying ROI can inclusively report the ligand bindings to a target protein in fast, intermediate and slow exchange regimes on nuclear magnetic resonance (NMR) time scale. The approach was successfully implemented and identified Angoroside C, Cinnamic acid and Harpagoside from the extract of Scrophularia ningpoensis Hemsl. as ligands binding to peroxisome proliferator-activated receptor γ. The proposed 2D NMR-based approach saves excess steps for sample processing and has a higher chance of detecting the weaker ligands in the complex extracts of medicinal herbs. We expect that this approach can be applied as an alternative to mining the potential ligands binding to a variety of target proteins from traditional Chinese medicines and herbal extracts.

Effectiveness of azvudine against severe outcomes among hospitalized COVID-19 patients in Xinjiang, China: a single-center, retrospective, matched cohort study.

BACKGROUND: Since the end of 2022, Azvudine was widely used to treat hospitalized coronavirus disease 2019 (COVID-19) patients in China. However, data on the real-world effectiveness of Azvudine against severe outcomes and post-COVID-19-conditions (PCC) among patients infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants was limited. This study evaluates the effectiveness of Azvudine in hospitalized COVID-19 patients during a SARS-CoV-2 Omicron BA.5 dominance period. METHODS: From 1 November 2022 to 1 July 2023, an SARS-CoV-2 Omicron BA.5 dominant period, we conducted a single-center retrospective cohort study based on hospitalized patients with laboratory-confirmed SARS-CoV-2 infection from a tertiary hospital in Shihezi, China. Patients treated with Azvudine and usual care were propensity-score matched (PSM) at a 1:1 ratio to a control group in which patients received usual care only, with matching based on covariates such as sex, age, ethnicity, number of preexisting conditions, antibiotic use at admission, and baseline complete blood cell count. The primary outcomes were all-cause death and short-term (60 days) PCC post discharge. The secondary outcomes included the initiation of invasive mechanical ventilation and PCC at long-term post discharge (120 days). Cox proportional hazards (PH) regression models were employed to estimate the hazard ratios (HR) of Azvudine treatment for both all-cause death and invasive mechanical ventilation, and logistic regression models were used to estimate the odds ratios (OR) for short-term and long-term PCC. Subgroup analyses were performed based on a part of the matched covariates. RESULTS: A total of 2,639 hospitalized patients with SARS-CoV-2 infection were initially identified, and 2,069 ineligible subjects were excluded from analyses. After matching, 297 Azvudine recipients and 297 matched controls were eligible for analyses. The incidence rate of all-cause death was relatively lower in the Azvudine group than in control group (0.007 per person, 95% confidence interval [CI]: 0.001, 0.024 vs 0.128, 95% CI: 0.092, 0.171), and the use of Azvudine was associated with a significantly lower risk of death (HR: 0.049, 95% CI: 0.012, 0.205). Subgroup analyses suggested protection of Azvudine against the risks of all-cause death among men, age over 65, patients without the preexisting conditions, and patients with antibiotics dispensed at admission. Statistical differences were not observed between the Azvudine group and the control group for the risks of invasive mechanical ventilation or short and long-term PCC. CONCLUSIONS: Our findings indicated that Azvudine was associated with lower risk of all-cause death among hospitalized patients with Omicron BA.5 infection in a real-world setting. Further investigation is needed to explore the effectiveness of Azvudine against the PCC after discharge.

This study aims to evaluate the real-world effectiveness of Azvudine among hospitalized COVID-19 patients during a SARS-CoV-2 Omicron BA.5 dominant epidemic phase. Cox proportional hazards (PH) regression models were employed to estimate the hazard ratios (HR) for all-cause death. We found that the use of Azvudine was associated with a significantly reduced risk of all-cause death among hospitalized patients with SARS-CoV-2 infection.

A Comprehensive Study of the Association between LEPR Gene rs1137101 Variant and Risk of Digestive System Cancers.

Objective: The leptin receptor, encoded by the LEPR gene, is involved in tumorigenesis. A potential functional variant of LEPR, rs1137101 (Gln223Arg), has been extensively investigated for its contribution to the risk of digestive system (DS) cancers, but results remain conflicting rather than conclusive. Here, we performed a case-control study and subsequent meta-analysis to examine the association between rs1137101 and DS cancer risk. Methods: A total of 1,727 patients with cancer (gastric/liver/colorectal: 460/480/787) and 800 healthy controls were recruited. Genotyping of rs1137101 was conducted using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay and confirmed using Sanger sequencing. Twenty-four eligible studies were included in the meta-analysis. Results: After Bonferroni correction, the case-control study revealed that rs1137101 was significantly associated with the risk of liver cancer in the Hubei Chinese population. The meta-analysis suggested that rs1137101 is significantly associated with the risk of overall DS, gastric, and liver cancer in the Chinese population. Conclusion: The LEPR rs1137101 variant may be a genetic biomarker for susceptibility to DS cancers (especially liver and gastric cancer) in the Chinese population.

Assembly of core-shell Fe3O4 @CD-MOFs derived hollow magnetic microcubes for efficient extraction of hazardous substances: Plausible mechanisms for selective adsorption.

Hazardous heavy metals and organic substances removal is of great significance for ensuring the safety of aquatic-ecosystem, yet the highly effective and selective extraction always remains challenging. To address this problem, magnetic hollow microcubes were fabricated through thermal carbonization of Fe3O4-COOH@ Î³-CD-MOFs, and core-shell structured precursors were in-situ greenly constructed on a large scale via microwave-assisted self-assembly strategy. As noted, the development of secondary crystallization was utilized to achieve uniform dispersion of cores within MOFs frameworks and thus improved magnetic and adsorption ability of composites. Acquired magnetic Fe3O4 @HC not only can harvest excellent extraction of heavy metals (Cd, Pb, and Cu of 129.87, 151.05, and 106.98 mg·g-1) but also exhibit highly selective adsorption ability for cationic organics (separation efficiency higher than 95.0 %). Impressively, Fe3O4 @HC achieved outstanding adsorption (60-80 %) of Cd in realistic mussel cooking broth with no obvious loss in amino acid. Characterizations better offer mechanistic insight into the enhanced selectivity of positively charged pollutants can be attributed to synergistic effect of ions exchange and electrostatic interaction of abundant oxygen-containing functional groups. Our study provides a feasible route by rationally developing core-shell structured composites to promote the practical applications of sustainable water treatment and value-added utilization of processing by-products.

Design, synthesis and neuroprotective biological evaluation of novel HDAC6 inhibitors incorporating benzothiadiazinyl systems as cap groups.

Histone deacetylase 6 (HDAC6), as the key regulatory enzyme, plays an important role in the development of the nervous system. More and more studies indicate that HDAC6 has become a promising therapeutic target for CNS diseases. Herein we designed and synthesized a series of novel HDAC6 inhibitors with benzothiadiazinyl systems as cap groups and evaluated their activity in vitro and in vivo. Among them, compound 3 exhibited superior selective inhibitory activity against HDAC6 (IC50 = 5.1 nM, about 30-fold selectivity over HDAC1). The results of docking showed that compound 3 can interact well with the key amino acid residues of HDAC6. Compound 3 showed lower cytotoxicity (20 µM to SH-SY5Y cells, inhibition rate = 25.75%) and better neuroprotective activity against L-glutamate-induced SH-SY5Y cell injury model in vitro. Meanwhile, compound 3 exhibited weak cardiotoxicity (10 µM hERG inhibition rate = 17.35%) and possess good druggability properties. Especially, compound 3 could significantly reduce cerebral infarction from 49.87% to 32.18%, and similar with butylphthalide in MCAO model, indicating potential clinical application prospects for alleviating ischemic stroke-induced brain infarction.

Identifying Anti-NSCLC Bioactive Compounds in Scutellaria via 2D NMR-Based Metabolomic Analysis of Pharmacologically Classified Crude Extracts.

We presented a strategy utilizing 2D NMR-based metabolomic analysis of crude extracts, categorized by different pharmacological activities, to rapidly identify the primary bioactive components of TCM. It was applied to identify the potential bioactive components from Scutellaria crude extracts that exhibit anti-non-small cell lung cancer (anti-NSCLC) activity. Four Scutellaria species were chosen as the study subjects because of their close phylogenetic relationship, but their crude extracts exhibit significantly different anti-NSCLC activity. Cell proliferation assay was used to assess the anti-NSCLC activity of four species of Scutellaria. 1H-13C HSQC spectra were acquired for the chemical profiling of these crude extracts. Based on the pharmacological classification (PCA, OPLS-DA and univariate hypothesis test) were performed to identify the bioactive constituents in Scutellaria associated with the anti-NSCLC activity. As a result, three compounds, baicalein, wogonin and scutellarin were identified as bioactive compounds. The anti-NSCLC activity of the three potential active compounds were further confirmed via cell proliferation assay. The mechanism of the anti-NSCLC activity by these active constituents was further explored via flow cytometry and western blot analyses. This study demonstrated 2D NMR-based metabolomic analysis of pharmacologically classified crude extracts to be an efficient approach to the identification of active components of herbal medicine.

Fast joint parity measurement via collective interactions induced by stimulated emission.

Parity detection is essential in quantum error correction. Error syndromes coded in parity are detected routinely by sequential CNOT gates. Here, different from the standard CNOT-gate based scheme, we propose a reliable joint parity measurement (JPM) scheme inspired by stimulated emission. By controlling the collective behavior between data qubits and syndrome qubit, we realize the parity detection and experimentally implement the weight-2 and weight-4 JPM scheme in a tunable coupling superconducting circuit, which shows comparable performance to the CNOT scheme. Moreover, with the aid of the coupling tunability in quantum system, this scheme can be further utilized for specific joint entangling state preparation (JEP) with high fidelity, such as multiqubit entangled state preparation for non-adjacent qubits. This strategy, combined with the superconducting qubit system with tunable couplers, reveals tremendous potential and applications in the surface code architecture without adding extra circuit elements. Besides, the method we develop here can readily be applied in large-scale quantum computation and quantum simulation.

Insights into serum metabolic biomarkers for early detection of incident diabetic kidney disease in Chinese patients with type 2 diabetes by random forest.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD) worldwide. Early detection is critical for the risk stratification and early intervention of progressive DKD. Serum creatinine (sCr) and urine output are used to assess kidney function, but these markers are limited by their delayed changes following kidney pathology, and lacking of both sensitivity and accuracy. Hence, it is essential to illustrate potential diagnostic indicators to enhance the precise prediction of early DKD. A total of 194 Chinese individuals include 30 healthy participants (Stage 0) and 164 incidents with type 2 diabetes (T2D) spanning from DKD's Stage 1a to 4 were recruited and their serums were subjected for untargeted metabolomic analysis. Random forest (RF), a machine learning approach, together with univariate linear regression (ULR) and multivariate linear regression (MvLR) analysis were applied to characterize the features of untargeted metabolites of DKD patients and to identify candidate DKD biomarkers. Our results indicate that 2-(α-D-mannopyranosyl)-L-tryptophan (ADT), succinyladenosine (SAdo), pseudouridine and N,N,N-trimethyl-L-alanyl-L-proline betaine (L-L-TMAP) were associated with the development of DKD, in particular, the latter three that were significantly elevated in Stage 2-4 T2D incidents. Each of the four metabolites in combination with sCr achieves better performance than sCr alone with area under the receiver operating characteristic curve (AUC) of 0.81-0.91 in predicting DKD stages. An average of 3.9 years follow-up study of another cohort including 106 Stage 2-3 patients suggested that "urinary albumin-to-creatinine ratio (UACR) + ADT + SAdo" can be utilized for better prognosis evaluation of early DKD (average AUC = 0.9502) than UACR without sexual difference.

HDAC6-selective inhibitor CAY10603 ameliorates cigarette smoke-induced small airway remodeling by regulating epithelial barrier dysfunction and reversing.

BACKGROUND: Small airway remodelling is a vital characteristic of chronic obstructive pulmonary disease (COPD), which is mainly caused by epithelial barrier dysfunction and epithelial-mesenchymal transition (EMT). Recent studies have indicated that histone deacetylase 6 (HDAC6) plays an important role in the dysregulation of epithelial function. In this study, we investigated the therapeutic effects and underlying mechanisms of an inhibitor with high selectivity for HDAC6 in COPD. METHODS: Cigarette smoke (CS) exposure was used to establish a CS-induced COPD mouse model. CAY10603 at doses of 2.5 and 10 mg/kg was injected intraperitoneally on alternate days. The protective effects of CAY10603 against CS-induced emphysema, epithelial barrier function and small airway remodeling were evaluated using hematoxylin and eosin (H&E) staining, Masson's trichrome staining, immunohistochemical staining, and western blot. The human lung bronchial epithelial cell line (HBE) was used to elucidate the underlying molecular mechanism of action of CAY10603. RESULTS: HDAC6 levels in the lung homogenates of CS-exposed mice were higher than that those in control mice. Compared to the CS group, the mean linear intercept (MLI) of the CAY10603 treatment group decreased and the mean alveolar number (MAN)increased. Collagen deposition was reduced in groups treated with CAY10603. The expression of α-SMA was markedly upregulated in the CS group, which was reversed by CAY10603 treatment. Conversely, E-cadherin expression in the CS group was further downregulated, which was reversed by CAY10603 treatment. CAY10603 affects the tight junction protein expression of ZO-1 and occludin. ZO-1 and occludin expression were markedly downregulated in the CS group. After CAY10603treatment, the protein expression level of ZO-1 and occludin increased significantly. In HBE cells, Cigarette smoke extract (CSE) increased HDAC6 levels. CAY10603 significantly attenuated the release of TGF-ß1 induced by CSE. CAY10603 significantly increased the E-cadherin levels in TGF-ß1 treated HBE cells, while concurrently attenuated α-SMA expression. This effect was achieved through the suppression of Smad2 and Smad3 phosphorylation. CAY10603 also inhibited TGF-ß1 induced cell migration. CONCLUSIONS: These findings suggested that CAY10603 inhibited CS induced small airway remodelling by regulating epithelial barrier dysfunction and reversing EMT via the TGF-ß1/Smad2/3 signalling pathway.

A narrative review of the role of HDAC6 in idiopathic pulmonary fibrosis.

Background and Objective: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible condition characterized by the deposition of extracellular matrix resulting from repetitive damage to the alveolar epithelium. These injuries, along with dysregulated wound repair and fibroblast dysfunction, lead to continuous tissue remodeling and fibrosis, eventually resulting in end-stage pulmonary fibrosis. Currently, there is no specific pharmacological treatment available for IPF. The role of inflammation in the development of IPF is still a topic of debate, and it is sometimes considered incidental to fibrosis. Over the past decade, macrophages have emerged as significant contributors to the pathogenesis of fibrosis. M1 macrophages are responsible for wound healing following alveolar epithelial injury, while M2 macrophages are involved in resolving wound repair and terminating the inflammatory response in the lungs. Various studies provide evidence that M2-like macrophages contribute to the abnormal fibrogenesis. In recent years, there has been growing interest in understanding macrophage polarization and its role in the development of pulmonary fibrosis. Histone deacetylase 6 (HDAC6), a member of the HDAC family with two functional deacetylase structural domains and a ubiquitin-binding zinc finger structural domain (ZnF-BUZ), plays a crucial role in pulmonary fibrosis. This article explores the role of HDAC6 in pulmonary fibrosis and evaluates its potential as a treatment approach for IPF. Methods: PubMed, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, China Biomedical Literature Service System (CBMdisc) and Web of Science were searched to obtain researches, published in English and Chinese, until July 2023. The search was performed using specific keywords such as Histone deacetylase 6, HDAC6, Idiopathic pulmonary fibrosis, IPF, fibrosis. Key Content and Findings: HDAC6 has diverse effects on physiological processes, including the NLRP3 inflammasome, epithelial-mesenchymal transition, the TGFß-PI3K-AKT pathway, macrophage polarization and TGF-ß-Smad signaling pathway, due to its unique structure. HDAC6 has been found to enhance the inflammatory response and fibrosis of lung tissues, contributing to the development of IPF. Conclusions: In the future, HDAC6 inhibitors are expected to play a crucial role in the treatment of fibrotic disorders and should be studied further deserves to pursue in future research.

Invasive mucinous adenocarcinoma of the lung with bronchorrhea - A marked reduction volume of sputum after SARS-CoV-2 infection.

Bronchorrhea is a watery sputum volume of at least 100 mL/day, which is commonly associated with lung malignancies. We report a 57-year-old woman was admitted to the hospital with a cough, profuse sputum. Chest CTs showed crazy paving pattern and lung nodules. Cell nests were visible on the Thinprep Cytologic Test. The case was considered an invasive mucinous adenocarcinoma of the lung combined with bronchorrhea. Significantly, the sputum volume declined rapidly and did not rise again when the patient was diagnosed with COVID-19 and treated with nirmatrelvir/ritonavir. This case is suggestive of studies related to regulatory mediators associated with bronchorrhea.

IL-6 gene polymorphism predicts PEGylated IFN-α treatment response in hepatitis B surface antigen-positive chronic hepatitis B patients.

Background: Genetic polymorphism can affect the response to antiviral therapy of chronic hepatitis B (CHB) patients. Objective: The study examined the genetic association of the IL-6 rs1800796 polymorphism with PEGylated IFN-α (PegIFN-α) treatment response in hepatitis B surface antigen (HBsAg)-positive CHB patients. Methods: Direct sequencing was done for the genotyping of the rs1800796 polymorphism in the serum of CHB patients. Results: More patients with combined response (n = 95) carried IL-6 rs1800796 GC genotypes, while CC genotype carriers possessed reduced HBeAg seroconversion rate and high values of hepatitis B virus DNA. Baseline HBsAg and HBeAg and IL-6 rs1800796 CC genotype were independently related to PegIFN-α treatment response. Conclusion: Detection of the IL-6 rs1800796 genotype in CHB patients may have potential guiding significance for PegIFN-α response.

Catalytic Asymmetric P-H Insertion Reactions.

Albeit notable endeavors in enantioselective carbene insertion into X-H bonds (X = C, O, N, S, Si, B), the catalytic asymmetric P-H insertion reactions still stand for a long-lasting challenge. By merging transition-metal catalysis with organocatalysis, we achieve a scalable enantioselective P-H insertion transformation between diazo pyrazoleamides and H-phosphine oxides that upon subsequent reduction delivers a wide variety of optically active ß-hydroxyl phosphine oxides in good yields with high enantioselectivity. The achiral copper catalyst fosters the carbenoid insertion into the P-H bond, while the chiral cinchona alkaloid-derived organocatalyst controls the subsequent enantioselective outcome. Density functional theory (DFT) calculations further reveal that the copper catalyst chelates to the organocatalyst, enhances its acidity, and accordingly promotes the enantioselective proton transfer. Our work showcases the potential of combining transition-metal catalysis with organocatalysis to realize elusive asymmetric reactions.

Antibiotic resistance genes in constructed wetlands: Driving indicators and risk assessment.

Constructed wetlands (CWs) were responsible for the in-depth purification of wastewater, providing an ideal environment for the transport, acquisition, and dissemination of antibiotic resistance genes (ARGs). A better understanding of influencing factors and risks of ARGs in CWs was deemed indispensable. In this research, the abundance of ARGs and mobile genetic elements (MGEs) was determined to be higher in summer and spring, ranging from 53.7 to 8.51 × 106 and 30.9-6.02 × 106 copies/mL, respectively. Seasonal variation significantly influenced the abundance of ARGs and MGEs, as well as the co-occurrence patterns among ARGs, MGEs and bacteria. However, the environmental gradients, from the influent (CW01) to the effluent (CW10), did not impose significant effects on the abundance of ARGs and MGEs. Furthermore, the ratios of pathogenic bacteria to ARG hosts and ARG risks index decreased by 50.4% and 88.54% along with the environmental gradients, indicating that CWs could act as barriers to the transfer of ARGs. Partial least squares-path modeling (PLSPM) revealed that temperature was the main driving factor of ARGs, followed by MGEs, stable and differential bacteria. This finding effectively and innovatively explored the driving indicators for the variations and risks of ARGs caused by spatial-temporal variations, providing new insights into the evaluation and control of ARGs in CWs.

Influenza vaccine effectiveness against influenza A during the delayed 2022/23 epidemic in Shihezi, China.

After the temporary end of COVID-19 in China in February 2023, the influenza epidemic peaked in March across many Chinese places. We recruited a total of 258 all-age subjects presenting influenza-like illness (ILI) in Shihezi city, China from January 1 to March 16, 2023, and tested for influenza virus infection. Using a test-negative design, we assessed influenza vaccine effectiveness (VE) of 56.3% (95% CrI: 13.6, 73.6) against medically attended, influenza illness during the delayed 2022/23 influenza epidemic. The findings contributed to the continuous monitoring of the influenza vaccine performance across the world, especially in the "post-COVID" pandemic era.

Visible-Light-Induced Carbene Insertion into P-H Bonds between Acylsilanes and H-Phosphorus Oxides.

An intriguing visible-light-induced strategy has been established for the P-H insertion reaction between acylsilanes and H-phosphorus oxides that, upon a subsequent acidic process, deliver a wide variety of α-hydroxyphosphorus oxides in good yields (up to 93% yield). The metal-free protocol represents a unique example of P-H insertion for C-P bond formation through in situ generation of siloxycarbenes. This methodology features the advantages of operational simplicity, mild conditions, broad substrate scope, and column free in gram-scale synthesis.

GIPMA: Global Intensity-Guided Peak Matching and Alignment for 2D 1H-13C HSQC-Based Metabolomics.

Two-dimensional (2D) 1H-13C heteronuclear single quantum coherence (HSQC) has been increasingly applied to metabolomics studies because it can greatly improve the resolving capability compared with one-dimensional (1D) 1H NMR. However, preprocessing methods such as peak matching and alignment tools for 2D NMR-based metabolomics have lagged behind similar methods for 1D 1H NMR-based metabolomics. Correct matching and alignment of 2D NMR spectral features across multiple samples are particularly important for subsequent multivariate data analysis. Considering different intensity dynamic ranges of a variety of metabolites and the chemical shift variation across the spectra of multiple samples, here, we developed an efficient peak matching and alignment algorithm for 2D 1H-13C HSQC-based metabolomics, called global intensity-guided peak matching and alignment (GIPMA). In GIPMA, peaks identified in all spectra are pooled together and sorted by intensity. Chemical shift of a stronger peak is regarded to be more accurate and reliable than that of a weaker peak. The strongest undesignated peak is chosen as the reference of a new cluster if it is not located within the chemical shift tolerance of any existing peak cluster (PC), or otherwise it is matched to an existing PC and the aligned chemical shift of the PC is updated as the intensity-weighted average of the chemical shifts of all peaks in the cluster. Setting an optimum chemical shift tolerance (Δδo) is critical for the peak matching and alignment across multiple samples. GIPMA dynamically searches for and intelligently selects the Δδo for peak matching to maximize the number of valid peak clusters (vPC), that is, spectral features, among multiple samples. By GIPMA, fully automatic peakwise matching and alignment do not require any spectrum as initial reference, while the chemical shift of each PC is updated as the intensity-weighted average of the chemical shifts of all peaks in the same PC, which is warranted to be statistically more accurate. Accurate chemical shifts for each representative spectral feature will facilitate subsequent peak assignment and are essential for correct metabolite identification and result interpretation. The proposed method was demonstrated successfully on the spectra of six model mixtures consisting of seven typical metabolites, yielding correct matching of all known spectral features. The performance of GIPMA was also demonstrated on 2D 1H-13C HSQC spectra of 87 real extracts of 29 samples of five Dendrobium species. Hierarchical cluster analysis (HCA) and principal component analysis (PCA) of the 87 matched and aligned spectra by GIPMA generates correct classification of the 29 samples into five groups. In summary, the proposed algorithm of GIPMA provided a practical peak matching and alignment method to facilitate 2D NMR-based metabolomics studies.

Effect of Different Processing Methods on the Chemical Constituents of Scrophulariae Radix as Revealed by 2D NMR-Based Metabolomics.

Scrophulariae Radix (SR) is one of the oldest and most frequently used Chinese herbs for oriental medicine in China. Before clinical use, the SR should be processed using different methods after harvest, such as steaming, "sweating", and traditional fire-drying. In order to investigate the difference in chemical constituents using different processing methods, the two-dimensional (2D) 1H-13C heteronuclear single quantum correlation (1H-13C HSQC)-based metabolomics approach was applied to extensively characterize the difference in the chemical components in the extracts of SR processed using different processing methods. In total, 20 compounds were identified as potential chemical markers that changed significantly with different steaming durations. Seven compounds can be used as potential chemical markers to differentiate processing by sweating, hot-air drying, and steaming for 4 h. These findings could elucidate the change of chemical constituents of the processed SR and provide a guide for the processing. In addition, our protocol may represent a general approach to characterizing chemical compounds of traditional Chinese medicine (TCM) and therefore might be considered as a promising approach to exploring the scientific basis of traditional processing of TCM.

Synthesis and structure-activity relationship of thiol-based histone deacetylase 6 inhibitors.

Selective histone deacetylase 6 (HDAC6) inhibitors are safe and well-tolerated with less off-target effect. However, most available HDAC6 inhibitors contain hydroxamate as a zinc-binding group (ZBG), and their unfavorable pharmacokinetic properties along with potential genotoxicity limited wide application in diverse diseases. Therefore, we designed and synthesized a series of selective HDAC6 inhibitors utilizing thiol as the ZBG and discussed their structure-activity relationship based on molecular docking. In particular, compound 21, obtained by constantly step-by-step simplification and evolution based on Ricolinostat, a specific HDAC6 inhibitor in Phase II, unexpectedly showed high selectivity (29-fold) and moderate potency (73 nM). Utilizing pyrimidine as a linker in thiol-based HDAC6 inhibitors produces an utterly novel structure, which might display different pharmacokinetic properties and genotoxicity.

Hypolipidemic activity and safety evaluation of a rhamnan-type sulfated polysaccharide-chromium (III) complex.

BACKGROUND: Hyperlipidaemia is a chronic disorder characterized by imbalance of energy metabolism and high blood lipid level. The rhamnan-type sulfated polysaccharide is an excellent metal-ion chelating ligands. In this study, hypolipidemic activity and safety evaluation of a rhamnan-type sulfated polysaccharide-chromium (III) complex (RSPC) were studied. METHODS: Scanning electron microscopy (SEM) and atomic force microscopy (AFM) were used to characterize the structure of RSPC. The effects of the RSPC on lipid metabolism in hyperlipidemic mice were evaluated by lipid contents, histopathological observation, immunofluorescent analysis, and adipocytokine levels. Moreover, sub-acute toxicity evaluation of RSPC was carried out on ICR mice. RESULTS: SEM and AFM further demonstrated formation of the polysaccharide-chromium (III) complex and revealed the intertwined network of RSPC. The RSPC significantly (p < 0.05) regulated lipid levels in the mice. The RSPC inhibited over-growth of adipocytes and reduced inflammatory infiltration induced by hyperlipidemia. The RSPC promoted differentiation of white adipose tissue into beige adipocytes and increased expression of uncoupling protein 1 (UCP1), thereby eliminating fat accumulation. Moreover, RSPC (5 mg/kg for mice; equivalent to 924 µg/d for adults) promoted secretion of adiponectin and suppressed resistin, leptin, and tumor necrosis factor alpha. Sub-acute toxicity evaluation showed that 1500 mg/kg of RSPC exhibited no apparent adverse effects on the mice. CONCLUSION: These results indicated that RSPC could be safely used to prevent hyperlipidemia and inflammation and may provide a new idea for the prevention of hyperlipidaemia and the related metabolic disorders.